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Cited by 190Viral-associated cancers and disordersCancer, Hypoxia, and MetabolismFolate and B Vitamins Research

Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation

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Wang, Liang Wei, Shen, Hongying, Nobre, Luis, Ersing, Ina, Paulo, Joao A., Trudeau, Stephen, Wang, Zhonghao, Smith, Nicholas A. +9 more·2019·Cell Metabolism
DOI 10.1016/j.cmet.2019.06.003PMC PMC6720460
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Abstract

Epstein-Barr virus (EBV) causes Burkitt, Hodgkin, and post-transplant B cell lymphomas. How EBV remodels metabolic pathways to support rapid B cell outgrowth remains largely unknown. To gain insights, primary human B cells were profiled by tandem-mass-tag-based proteomics at rest and at nine time points after infection; >8,000 host and 29 viral proteins were quantified, revealing mitochondrial remodeling and induction of one-carbon (1C) metabolism. EBV-encoded EBNA2 and its target MYC were required for upregulation of the central mitochondrial 1C enzyme MTHFD2, which played key roles in EBV-driven B cell growth and survival. MTHFD2 was critical for maintaining elevated NADPH levels in infected cells, and oxidation of mitochondrial NADPH diminished B cell proliferation. Tracing studies underscored contributions of 1C to nucleotide synthesis, NADPH production, and redox defense. EBV upregulated import and synthesis of serine to augment 1C flux. Our results highlight EBV-induced 1C as a potential therapeutic target and provide a new paradigm for viral onco-metabolism.

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  • Proteomic data confirm general upregulation of proteins involved in beta-oxidation, plasmalogen and VLCFA synthesis (ELOVL1) with concurrent downregulation of ABCD1.

    “data retrieved and reanalyzed from a temporal proteomic data set, obtained during EBV infection of primary human B cells by Wang and colleagues23, confirmed the general upregulation of proteins involved in β-oxidation, plasmalogen and VLCFA synthesis (ELOVL1) with concurrent downregulation of ABCD1 (Supplementary Fig. 3a).”

    From Peroxisomal very long-chain fatty acid transport is targeted by herpesviruses and the antiviral host response (2022) · cites this paper as [23]

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Authors
Wang, L. W., Shen, H., Nobre, L., Ersing, I., Paulo, J. A., Trudeau, S., Wang, Z., Smith, N. A., Ma, Y., Reinstadler, B., Nomburg, J., Sommermann, T., Cahir-McFarland, E., Gygi, S. P., Mootha, V. K., Weekes, M. P., & Gewurz, B. E.
Affiliations
  • Brigham and Women's Hospital (US)
  • Broad Institute (US)
  • Harvard University (US)
  • University of Cambridge (GB)
Corresponding author
  • Weekes, Michael P.
  • Gewurz, Benjamin E.
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2019-09
Volume
30
Issue
3
Pages
539-555.e11
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2019.06.003
PMC
PMC6720460
OpenAlex
W2954390295
Cited by
190
References
10
Citations by year
2026: 25 · 2025: 28 · 2024: 32 · 2023: 28 · 2022: 31 · 2021: 26 · 2020: 15 · 2019: 5
FWCI
8.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • National Institutes of Health (RO1 AI137337)
  • American Cancer Society
  • Burroughs Wellcome Fund
  • Agency for Science, Technology and Research (K01 DK098285, 108070/Z/15/Z)
  • Massachusetts General Hospital
  • Wellcome Trust
  • Janssen Pharmaceuticals
  • Howard Hughes Medical Institute
Topics
  • Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
Keywords
Epstein-Barr virus, one-carbon metabolism, B cell transformation, MTHFD2, EBNA2, c-Myc, NADPH, mitochondrial remodeling, serine metabolism, nucleotide synthesis, redox defense, Burkitt lymphoma, B-cell lymphoma
MeSH terms
Aminohydrolases, B-Lymphocytes, Cell Transformation, Viral, Herpesvirus 4, Human, Female, Folic Acid, Glycolysis, Humans, Lymphocyte Activation, Methylenetetrahydrofolate Dehydrogenase (NADP), Mitochondria, NADP, Oxidation-Reduction, Serine, Proto-Oncogene Proteins c-myc, Epstein-Barr Virus Nuclear Antigens, Epstein-Barr Virus Infections, Proteome, HEK293 Cells, Multifunctional Enzymes

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